YEBEH-03826; No. of pages: 6; 4C: Epilepsy & Behavior xxx (2014) xxx–xxx

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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh

Targeted Review

Key issues in addressing the comorbidity of Attention Deficit Hyperactivity and disorder and pediatric epilepsy Jay A. Salpekar ⁎, Gaurav Mishra Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, George Washington University School of Medicine, Washington, DC, USA

a r t i c l e

i n f o

Article history: Received 7 March 2014 Revised 22 April 2014 Accepted 23 April 2014 Available online xxxx Keywords: Pediatrics ADHD Epilepsy Treatment Diagnosis

a b s t r a c t Attention deficit hyperactivity disorder (ADHD) is a common comorbidity of epilepsy encountered by clinicians. However, relatively little information is available to guide optimal diagnostic and treatment strategies. Differentiating ADHD from effects of epilepsy requires careful history taking and emphasis upon characteristic symptoms and course of illness. Rating scales for ADHD are well validated and may aid clinical management. Use of antiepileptic drugs may cause cognitive or behavioral side effects yet may improve behavior in some cases. Historically, clinicians have been hesitant to treat ADHD comorbidity for fear of lowering the seizure threshold. However, an aggregate of recent evidence now suggests that stimulants may be well tolerated and effective for ADHD comorbid with epilepsy. Studies that further clarify pathophysiology and treatment outcomes are needed in order to enhance clinical efficacy and quality of life for this population. © 2014 Elsevier Inc. All rights reserved.

Key questions 1. How common is attention deficit hyperactivity disorder (ADHD) in children and adolescents with epilepsy?

2. How can seizures and related inattention be distinguished from ADHD?

3. Do antiepileptic drugs cause problems with attention and concentration?

4. Is stimulant medicine safe in patients with epilepsy and comorbid ADHD?

5. What research is needed to advance care and treatment of ADHD in pediatric epilepsy?

1. How common is ADHD in children and adolescents with epilepsy? Attention deficit hyperactivity disorder (ADHD) is a common illness in pediatrics and also represents the most common psychiatric comorbidity associated with pediatric epilepsy [1,2]. Attention deficit hyperactivity disorder is usually identified in a school-aged population aged 6–12 years and is characterized by a constellation of symptoms that encompass inattention, hyperactivity, and impulsivity. Despite the ⁎ Corresponding author at: Department of Psychiatry and Behavioral Sciences, Children's National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010, USA. Tel.: +1 202 476 3932; fax: +1 202 476 5039. E-mail address: [email protected] (J.A. Salpekar).

heterogeneity of clinical presentations, ADHD may represent one of the most reliably applied diagnoses in all of psychiatry. The interrater reliability for ADHD among psychiatry clinicians and researchers is excellent and favorably compares with diagnostic agreement for mood disorders or psychosis in the pediatric population [3]. A key point to emphasize for clinicians and caregivers is that ADHD is common, and very likely to be encountered in epilepsy clinical care centers. Even conservatively designed epidemiology studies report a worldwide prevalence of ADHD in 3–6% of the pediatric population [4,5]. However, ADHD is overrepresented in epilepsy, with several studies reporting prevalence ranging from 30 to 40% [6]. A diagnosis of epilepsy has been associated with a 2.5–5.5 times higher chance of having co-occurring ADHD. The predominantly inattentive subtype of ADHD may be especially common. In a clinical sample of chronic pediatric epilepsy, one group found inattentive subtype at 24%, combined subtype at 11%, and hyperactive/impulsive subtype at 2% [7]. However, a prospective research study noted the combined type of ADHD to be prevalent in 58% of a sample of pediatric epilepsy [8]. Another unique phenomenon in this population is the disappearance of usual gender differences in the prevalence of ADHD. Without epilepsy, ADHD is seen in school-aged children with a male to female ratio of 2–3:1; however, the ratio is 1:1 when comorbid with epilepsy [9]. The cooccurrence of both illnesses is so frequent that some investigators have posited a pathophysiologic overlap between the two conditions. A recent study compared 76 children and adolescents with recent-onset epilepsy with 62 healthy controls and found that 31% of the children with epilepsy had ADHD versus only 6% in the control group [10]. The intriguing aspect of this study is that, in most cases,

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Please cite this article as: Salpekar JA, Mishra G, Key issues in addressing the comorbidity of Attention Deficit Hyperactivity and disorder and pediatric epilepsy, Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.04.021

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ADHD preceded the first seizure. Along with other studies of populations with new-onset epilepsy, these findings suggest that ADHD may represent an intrinsic pathologic process. The ADHD in these cases cannot be attributed to medication side effect because, in most cases, antiepileptic drugs (AEDs) had not yet been initiated. Furthermore, inattention potentially resulting from the cumulative deleterious effects of chronic seizures would also be unlikely in a new-onset population. Recent studies have reinforced the possible transactional nature of epilepsy and ADHD. Children with ADHD not only have a higher chance of developing epilepsy in the future but also have increased severity of epilepsy [11]. Some hypotheses point to ADHD being a “successive comorbidity” to epilepsy, developing due to a lowered seizure threshold. In that manner, early onset of epileptiform discharges may interfere with the typical development of brain regions or networks associated with attention and impulsivity [12]. Ongoing epileptic seizures and subclinical epileptiform discharges may have lasting effects on attention and cognitive function. The impaired brain development would then yield ongoing impairment even when seizures are well controlled. A recent study supports the premise that the presence of ADHD symptoms at the time of epilepsy onset is a risk factor for atypical cognitive development in the future [13]. Recent advances in genetics and in neuroimaging studies have also suggested important overlaps between epilepsy and ADHD [14]. Attention deficit hyperactivity disorder is a highly heritable condition, and children with both ADHD and epilepsy are more likely to have mothers with ADHD [15]. Additionally, activation patterns in brain regions impacted in ADHD may be similar for children with or without epilepsy [16]. Impaired connectivity in attention networks may also be present in childhood absence epilepsy and be identified by neuropsychological tasks geared toward ADHD assessment [17]. Electroencephalographic (EEG) studies have furthered speculation regarding a physiologic overlap between the two conditions [18]. Several studies have shown a higher frequency of EEG abnormalities in patients with ADHD when compared with the general population [19,20]. Although sampling issues may confound generalizability, a handful of studies have found epileptiform complexes in 6–30% of the patients with ADHD and without epilepsy as compared with the rate of 3.5% in the general population [21–23]. One study reported a sample where 53% of children with ADHD had epileptiform abnormalities in overnight EEG readings [24]. The increase of resting theta waves in frontal regions seems to be a particularly consistent EEG abnormality found in patients with ADHD [25]. Abnormal alpha asymmetry [26] and a higher theta-to-beta ratio [27] have also been reported. It should be noted that implications of these abnormalities in terms of seizure occurrence or propagation in children with epilepsy are largely unknown. Although the implications are largely unknown, the presence of subclinical “nonconvulsive” epileptiform complexes, possibly occurring during seizure-free periods, may have significant effects on vigilance, memory, and processing speed. This phenomenon was described in the 1980s and referred to as transient cognitive impairment and was seen in nearly 50% of patients with epilepsy who also had frequent subclinical epileptiform discharges in the alert state [28]. Transient cognitive impairment can be detected by testing short-term memory and language and is detected during approximately one-third of epileptiform discharges in two-thirds of patients [29]. In this study, the resolution of these interictal discharges with AED treatment had a positive effect on attention and cognitive functioning, though the extent of interference by these discharges is still difficult to quantify [29]. Although a clear consensus is lacking, attempts have been made to correlate seizure types or localization with the incidence of ADHD. Epilepsy associated with frontal lobe seizure foci has been frequently associated with inattention and impulsivity—constituent symptoms of ADHD. Impulsivity, hyperactivity, irritability, and executive function deficiencies are also key features of ADHD and have been associated with prefrontal cortex dysfunction. Thus, it may be intuitive to suggest that ADHD may be more likely to occur in patients with frontal lobe seizure foci.

Overall, ADHD commonly cooccurs with pediatric epilepsy in up to one-third of cases or more. The overlap is significant to such a degree that common pathophysiology may be imputed. Frontal lobe seizure foci appear to present a significant risk, but overall network effects may similarly be awry and lead to ADHD symptoms. The differential diagnosis may be challenging, and factors such as sleep disruption and seizure severity may play important roles in the prevalence and impact of ADHD symptoms [30–32]. For clinicians, identification of potential ADHD is an important practicality that challenges optimal management of epilepsy. 2. How can seizures and related inattention be distinguished from ADHD? Symptoms of inattention and distractibility present challenges to clinicians attempting to differentiate ADHD from seizures. Subsyndromal problems with attention perhaps even associated with subclinical EEG abnormalities or nonconvulsive seizures may be difficult to differentiate from ADHD. Other attention issues that complicate diagnosis may be side effects of antiepileptic drugs (AEDs), preictal auras, or confusion associated with the postictal periods. Finally, specific seizure types, namely, absence seizures, may be very difficult to distinguish from state abnormalities of ADHD. The clearest course for clinicians attempting to characterize inattention is thorough history taking. Attention deficit hyperactivity disorder itself is a diagnosis based upon history and, in many cases, represents a diagnosis of exclusion. Epilepsy may similarly be a diagnosis based upon history as seizures may be uncommonly witnessed by clinicians, and physical exam findings are typically absent. Typical ADHD symptoms occur in multiple settings at home or at school and are usually only mitigated by high degrees of structure. Epilepsy may be less predictable, and symptoms may be more prominent in periictal time periods, especially if prodromes and postictal periods are liberally extended on the order of many hours or days. Key differences are found in Table 1. Some investigators have attempted to find unique symptoms or task performance that may more reliably identify either condition. A prospective study distinguished epilepsy and ADHD based upon performance on timed cognitive decision-making tasks and reaction times. Attention deficit hyperactivity disorder was characterized by impulsive errors and disinhibition on simple reaction time tasks, whereas patients with epilepsy had a generalized slower performance on complex decision-making tasks [33]. This suggests that ADHD may have inconsistent cognitive processing, while epilepsy may have more global slowed function. The authors also note that many performances on psychological tasks did not differ between epilepsy and ADHD. Absence seizures can account for nearly 10–15% of all childhood-onset epilepsies and represent a particularly challenging differential diagnosis. Absence seizures may, on the surface, appear very similar to lapses of attention that characterize ADHD. Even beyond the discrete seizure episodes, children with absence epilepsy demonstrate higher rates of distractibility and more problems with homework and require more educational resources compared with controls [34]. A cumulative effect of cognitive dysfunction makes it harder to differentiate the inattention that may result from chronic absence epilepsy from the inattentive phases of ADHD. Some studies have implicated similar cortical–subcortical networks in the pathophysiology of absence seizures and attentional disorders [35]. A clever study done by Williams and colleagues attempted to identify behavioral symptoms that suggest specific associations with either absence seizures or ADHD. A list of 40 behavioral symptoms was assessed from observers. The strongest specific predictor of seizures was the occurrence of “change of breathing” and “glassy eyes”. The strongest predictor of ADHD included “fidgeting”, which was not commonly seen in patients with epilepsy [36]. For ADHD, multiple rating scales have been developed that very effectively measure the presence and severity of ADHD. Rating scales may be nonspecific, especially with diagnostic confounds potentially

Please cite this article as: Salpekar JA, Mishra G, Key issues in addressing the comorbidity of Attention Deficit Hyperactivity and disorder and pediatric epilepsy, Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.04.021

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Table 1 Selected symptoms possibly differentiating ADHD from epilepsy. ADHD

Epilepsy

Symptoms occur throughout the day and in multiple environments More prominent hyperactivity, restlessness Disorganization prominent Impulsivity may be more pronounced in unstructured environments or in situations requiring waiting Social relationships may be globally impaired Somewhat consistent inability to follow multistep commands

Symptoms may predominantly occur within periictal time periods Fidgeting less common, though automatisms may be present Organizational ability may not be affected Impulsivity may not be prominent Social impairment often due to social anxiety or isolation Fluctuating ability to follow multistep commands

present in epilepsy, and are best used as screening tools that may contribute to clinical evaluation. Normative data are available for four rating scales, and the tools may also be effective in identifying other psychiatric conditions as well. Such rating scales may readily be completed by parents in an office setting and are useful tools for clinicians seeking a more structured approach to diagnosis. The majority of rating scales also have versions for teachers to complete which may complement parent ratings. Most are proprietary scales, with the exception of the SNAPIV scale, which is publically available. Examples are described in Table 2. 3. Do antiepileptic drugs cause problems with attention and concentration? Antiepileptic drugs may have positive behavioral effects, especially regarding impulse control and mood stability [37]. Some antiepileptic drugs are particularly useful primary treatments for bipolar disorder and effective adjunctive treatments for depression. By and large, anticonvulsant usage that successfully improves seizure control may also improve cognitive function. Unfortunately, some AEDs may adversely affect attention and concentration, complicating efforts to specifically diagnose ADHD. A clinician's first step is to optimize seizure control and minimize polypharmacy and drug–drug interactions whenever possible. Although any AED may potentially be poorly tolerated or lead to confusion or sedation in high doses, some AEDs seem particularly associated with attention and concentration problems [38,39]. Any medication that causes sedation or drowsiness may also lead to disrupted concentration. Phenobarbital has long been known to cause sedation and even depression in vulnerable populations and may increase impulsivity errors on psychometric tests [40,41]. Topiramate is also commonly reported to cause cognitive slowing, word-finding problems, and, possibly, inattention [42,43]. With an aggressive titration schedule, topiramate has been reported to pose more pronounced cognitive side effects and may even cause depressive symptoms [44,45]. Details of potential attention difficulties related to commonly used antiepileptic drugs are listed in Table 3. 4. Is stimulant medicine safe in patients with epilepsy and comorbid ADHD? Despite the prominent cooccurrence of ADHD and epilepsy in pediatrics, treatment studies are uncommon. For many decades, conventional practice has held that stimulants may be risky in the context of epilepsy. Methylphenidate has been said to lower seizure threshold, leading to a FDA warning advising against the use of MPH products in patients with seizures [46], even though preclinical studies have shown seizures as a possible side effect only in overdoses. The fear of potentially lowering the seizure threshold has led to many clinicians avoiding the use of stimulants and, thus, undertreating comorbid ADHD. However, recent studies have shown that this concern may be unfounded. Stimulant medications including methylphenidate (MPH) appear to have a mechanism of at least partially blocking the presynaptic reuptake of dopamine and norepinephrine, thus prolonging catecholamine action in the synapse. There do not appear to be prominent effects on pathways for gamma-aminobutyric acid (GABA), glutamate, and aspartic acid, or at sodium or calcium channels, which have been associated with the pathophysiology of epilepsy [47]. In a minority of cases,

prolonged action of stimulant medications may lead to initial insomnia, and the resulting sleep deprivation could be posited to reduce the seizure threshold. Stimulants do not appear to have meaningful drug– drug interactions with commonly used antiepileptic medications. One academic effort suggests that lower basal dopamine may be associated with subclinical EEG abnormalities [48]. In that light, methylphenidate and other dopamine-enhancing stimulants appear to have some theoretical basis for lowering the seizure threshold. Although no large scale clinical trials have been done, several case series and small trials have been done with MPH. The largest open-label trial, with 119 children with epilepsy and ADHD, found no increase in seizures with MPH treatment [49]. Nearly all studies in the literature have been done with MPH, but a small post hoc review of clinical trial data as well as a retrospective review showed no increase in seizures in patients treated with atomoxetine [50,51]. One study that included patients with difficult-to-treat epilepsy found improved severity ratings based upon the Hague Seizure Severity Scale [52]. This effect was partially thought to be due to the effect of improved vigilance or alertness countering potential sedation related to AEDs. Selected clinical studies addressing MPH treatment of ADHD comorbid with pediatric epilepsy are listed in Table 4. A qualified consensus among existing studies suggests that when epilepsy is well controlled, i.e., less than one seizure a month, addition of MPH does not lead to an increase in seizures. However, low baseline seizure rates, small numbers of subjects, and short observation periods limit the power of these studies and therefore the generalizability of the conclusions. Highlighting this uncertainty, a recent crossover trial suggested that, over time, an increased daily risk of seizures correlated with higher OROS-MPH doses, although no adverse events occurred in the study [53]. It seems that, particularly in children with uncontrolled seizures, caution needs to be exercised [13]. However, given the marked academic and social sequelae of untreated ADHD, the risk/benefit profile even with poorly controlled epilepsy may still favor treatment with stimulants. 5. What research is needed to advance care and treatment of ADHD in pediatric epilepsy? Both epilepsy and ADHD individually have a huge impact on children and adolescents in multiple areas of their lives—academically, socially, recreationally, and developmentally. When both conditions are present, the effect may be magnified, especially in terms of a lower quality of life. However, very few prospective research studies have been done to evaluate etiology of this comorbidity or to clarify optimal treatment strategies. Sophisticated studies are lacking in terms of exploring the presence of EEG abnormalities in ADHD or of elucidating the role of dopamine in modulating seizure threshold. Pathophysiologic overlap may explain the overrepresentation of ADHD in pediatric epilepsy, but a specific etiologic mechanism is still elusive. The presence of epileptiform discharges in children with ADHD, e.g., rolandic spikes, may be related to increased impulsivity and raise important questions about ADHD pathophysiology [54]. Although some studies have found an increased frequency of ADHD in children with rolandic spikes, investigators were unable to establish a causal or even temporal relationship. Nevertheless, such efforts are groundbreaking and may inform understanding of ADHD pathophysiology with or without epilepsy. Further EEG studies in patients with ADHD and prominent

Please cite this article as: Salpekar JA, Mishra G, Key issues in addressing the comorbidity of Attention Deficit Hyperactivity and disorder and pediatric epilepsy, Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.04.021

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impulsivity are needed to establish if cooccurring pathogenesis exists and if comanagement can be improved. Recent advances in neuroimaging techniques have helped in clarifying white matter tracts linking specific brain regions such as the caudate nucleus and prefrontal cortex, both of which seem to be constituent elements of ADHD pathophysiology [55,56]. However, very little work has been done with imaging when ADHD is comorbid with epilepsy. This effort is clearly needed in order to explain how pathophysiology may vary from ADHD without epilepsy. Despite the intrigue offered by etiologic investigations, the primary challenge for patients and physicians is practical. Very little is known about optimal treatments for ADHD comorbid with pediatric epilepsy. Double-blind, randomized controlled trials with placebo controls

will be very useful in enabling clinicians to make informed decisions regarding treatment. Thus far, only small trials have been done, but a deliberate effort to establish treatment outcomes with class I clinical trial data will go a long way toward clarifying efficacy and tolerability in this population. Outcomes for ADHD as well as seizures will be important elements of such efforts. Ultimately, informed treatment strategies represent a significant gap in the literature, and results of such studies would be immediately of use to clinicians and their patients. Acknowledgments No grants or financial aid were received to support this review. Disclosures None of the authors has any conflict of interest to disclose.

Table 2 Rating scales for ADHD and other psychiatric conditions. Rating scale

Description

Reference

Child Symptom Inventory 4 (CSI-4) Child Behavior Checklist (CBCL) Behavior Assessment System for Children (BASC) Conners Parent/ Teacher Rating Scale ADHD Rating Scale Vanderbilt ADHD Rating Scale SNAP-IV Rating Scale

A broad-based psychopathology instrument

[57]

Parent, teacher, patient self-report measures for a variety of psychiatric conditions Parent, teacher, patient self-report measures for a variety of psychiatric conditions

[58]

Widely used parent and teacher report measure, established normative data DSM-based symptom questionnaire Parent and teacher reports, available to American Academy of Pediatrics members Comprehensive self-report scales, obtain free of charge at www.adhd.net

[60]

Key questions (answered) 1. How common is attention deficit hyperactivity disorder

[59]

2. [61] [62] [63]

3.

Table 3 Attention and behavioral side effects of antiepileptic drugs [48,64]. Antiepileptic drug

Potential side effects

Benzodiazepines Lacosamide Oxcarbazepine Phenobarbital

Confusion, disinhibition, cognitive impairment, irritability Memory impairment, behavioral dysregulation Impaired concentration, somnolence, improved behaviors Hyperactivity, poor attention, aggression, cognitive impairment — worse with higher doses Confusion, cognitive impairment affecting memory, motor, and mental speed. Affective dysregulation Cognitive impairment, behavioral difficulties, poor attention Cognitive slowing, difficulty in concentrating Cognitive impairment, poor attention, confusion; may be more pronounced with rapid dose titration Irritability, aggression, sedation, mania, psychosis

Phenytoin Gabapentin/ pregabalin Tiagabine Topiramate Zonisamide

4.

5.

(ADHD) in children and adolescents with epilepsy? Attention deficit hyperactivity disorder may be present in up to 40% of children and adolescents with epilepsy. How can seizures and related inattention be distinguished from ADHD? Distinguishing absence seizures and distractibility from ADHD may be very difficult. Children with absence seizures are more likely to have a glassy-eyed appearance, and children with ADHD are more likely to display fidgeting. Do antiepileptic drugs cause problems with attention and concentration? Phenobarbital and topiramate may have effects upon attention and concentration. However, so long as sedation is not prominent, most AEDs do not appear to pose a significant risk and may even improve symptoms of impulsivity. Is stimulant medicine safe in patients with epilepsy and comorbid ADHD? Stimulant medicine does not appear to increase risk of seizures in patients with stable epilepsy, defined as less than one seizure per month. Seizure risk of stimulants for patients with unstable epilepsy is unknown. What research is needed to advance care and treatment of ADHD in pediatric epilepsy? Neuroimaging to clarify etiology and pathophysiology and clinical trials yielding information for outcomes of seizures and ADHD will greatly contribute to treatment efforts.

Table 4 Selected studies of MPH in patients with ADHD and epilepsy. Reference

Study type

Subject number

Finding

Gonazalez-Heydrich et al. [53]

33 children with stable epilepsy

Gross-Tsur et al. [66]

Double-blind, placebo-controlled, crossover trial of OROS-MPH Double-blind, placebo-controlled, crossover Prospective comparison study

Gucuyenyer et al. [49]

Prospective uncontrolled study

Santos et al. [52]

Open label

Yoo et al. [67]

Open label

119 children with epilepsy or EEG abnormalities 22 children with poorly controlled epilepsy and varied epilepsy types 25 children with epilepsy and ADHD

Fosi et al. [68]

Retrospective

Wroblewski et al. [69]

Retrospective review

3 seizures in placebo group; 5 seizures in active treatment group No seizures in 4 weeks; MPH had no effect on blood levels of AEDs No significant difference in seizure occurrence over 8 weeks No change in seizure frequency. Baseline not well established Improvement in seizure severity rating; 4 with seizures in 3 months Improved quality-of-life rating, 2 drop outs from stimulant side effects; 2 seizures Improved ADHD symptoms with MPH; no clear worsening of seizures Trend toward lower seizure frequency in children treated with MPH

Feldman et al. [65]

10 children with standard dosing of 0.3-mg/kg BID 30 children with stable epilepsy

18 children with medically refractory epilepsy and ADHD 30 children with TBI

Please cite this article as: Salpekar JA, Mishra G, Key issues in addressing the comorbidity of Attention Deficit Hyperactivity and disorder and pediatric epilepsy, Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.04.021

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Please cite this article as: Salpekar JA, Mishra G, Key issues in addressing the comorbidity of Attention Deficit Hyperactivity and disorder and pediatric epilepsy, Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.04.021

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Please cite this article as: Salpekar JA, Mishra G, Key issues in addressing the comorbidity of Attention Deficit Hyperactivity and disorder and pediatric epilepsy, Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.04.021

Key issues in addressing the comorbidity of attention deficit hyperactivity disorder and pediatric epilepsy.

Attention deficit hyperactivity disorder (ADHD) is a common comorbidity of epilepsy encountered by clinicians. However, relatively little information ...
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